Autophagy inhibition-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis

Charlotte Hill, Juanjuan Li, Dian Liu, Franco Conforti, Christopher J Brereton, Liudi Yao, Yilu Zhou, Aiman Alzetani, Serena J Chee, Ben G Marshall, Sophie V Fletcher, David Hancock, Christian H Ottensmeier, Andrew J Steele, Julian Downward, Luca Richeldi, Xin Lu, Donna E Davies, Mark G Jones, Yihua Wang

Research output: Contribution to journalArticle

Abstract

Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here, we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial-mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (SNAI2), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. Our data suggest that reduced autophagy induces EMT of alveolar epithelial cells and can contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.

Original languageEnglish
Pages (from-to)591
JournalCell death & disease
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 7 2019

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    Hill, C., Li, J., Liu, D., Conforti, F., Brereton, C. J., Yao, L., Zhou, Y., Alzetani, A., Chee, S. J., Marshall, B. G., Fletcher, S. V., Hancock, D., Ottensmeier, C. H., Steele, A. J., Downward, J., Richeldi, L., Lu, X., Davies, D. E., Jones, M. G., & Wang, Y. (2019). Autophagy inhibition-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis. Cell death & disease, 10(8), 591. https://doi.org/10.1038/s41419-019-1820-x